Ferroptosis-driven immune remodeling in heart failure: the central role of macrophage reprogramming and impaired efferocytosis

Progressive myocardial remodeling in heart failure (HF) is sustained by unresolved inflammation and defective tissue repair. Ferroptosis, characterized by iron-dependent lipid peroxidation, has emerged as a critical source of cardiomyocyte death in failing hearts. Importantly, ferroptotic cells release damage-associated molecular patterns and oxidized phospholipids that alter macrophage activation states and perpetuate inflammatory signaling. Under physiological conditions, macrophage-mediated efferocytosis ensures rapid clearance of dying cells and promotes inflammation resolution. In HF, however, excessive cell death burden, redox imbalance, and metabolic stress collectively impair efferocytic capacity. The resulting accumulation of apoptotic and ferroptotic debris reinforces inflammatory activation and extracellular matrix deposition, generating a vicious cycle of injury and fibrosis. Here, we synthesize evidence supporting a ferroptosis-centered immune remodeling loop and define efferocytosis as a regulatory checkpoint in disease progression. We also evaluate emerging therapeutic strategies aimed at interrupting this cycle through iron modulation, antioxidant delivery, metabolic reprogramming, and bioengineered targeting systems. Understanding this integrated axis may uncover novel intervention points for halting HF progression.